Epigenetic modifications are increasingly understood and of increasing prognostic and predictive relevance. Normally functioning DNA methyltransferases silence genes by meth- ylating promoter regions. Thought to be an early step in carcinogenesis, abnormal methylation activity results in inactivation of tumor suppressor genes contributing to car- cinogenesis, metastasis, invasiveness, and deregulation of the cell cycle. Methylation status has prognostic and thera- peutic potential. The concept of demethylating therapy started in myleodysplastic syndrome and is being adapted to solid tumors trials.
Many tumors have well-characterized, high incidence of hypermethylation at specific promoter regions. Hypermethylation in HNSCCs has been demonstrated at many genes, including those of p16, E-cadherin, MGMT, DAPK1, RAR beta, and cyclin A1 among many [71, 72]. The Ras/P13K/AKT pathway is thought to be a major factor in radiation sensitivity, and hypermethylation of RASSF1A and RASSF2A in a study of 482 samples was correlated with response to radiation [73].
Methylation of the CDH-1 promoter may have prognostic significance having been observed to correlate with overall survival [74].
Conclusion
Current research and patient care are influenced by rapidly advancing knowledge of the molecular biology of head and neck cancer, and the complexity of interconnecting pathways
from cell surface receptors to transcriptional activation of genes mediating uncontrolled cellular proliferation and survival. Molecular target identification and an array of new therapeutics present challenges to the standard methodolo- gies for clinical trial design, evaluation of efficacy and toxic- ity. Risk stratification based on molecular prognostic and predictive markers is next on the horizon for advancing the field. This chapter has focused on markers with potential for testing in large validation clinical trials. As yet, no one marker has validated predictive capacity of utility in the selection of therapy for individuals with head and neck cancer. HPV-16 appears to be prognostic for better outcome while high EGFR expression is prognostic for poor outcome.
Validated diagnostic tests that are widely available and collaboration among investigators are additional future chal- lenges in biomarker research for head and neck cancer.
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J. Bernier (ed.), Head and Neck Cancer: Multimodality Management, 169
DOI 10.1007/978-1-4419-9464-6_10, © Springer Science+Business Media, LLC 2011
Abstract Tumor hypoxia, or the condition of low oxygen, is a key factor for tumor progression and treatment resis- tance. Hypoxic areas arise as a result of an imbalance between the supply and consumption of oxygen. Cellular responses to hypoxia are orchestrated through activation of the hypoxia-inducible factor family of transcription factors (HIFs). There are several approaches for detecting tumor hypoxia in head and neck cancers (HNC). Direct oxygen measurements in tissues with Eppendorf-pO2 histography have been used, but this method is invasive. Recent studies have focused on molecular markers of hypoxia, such as HIF-1 and carbonic anhydrase isozyme IX (CA-IX), and on developing noninvasive imaging techniques. Hypoxia appears to be prognostic for outcome in HNC. Several stud- ies have shown that low pO2 in tumor, high HIF-1, Glut-1 and CA-IX expression, serum level of osteopontin correlated with treatment outcomes in HNC patients treated with RT or chemoradiotherapy.
Several strategies have been used to overcome hypoxia- induced treatment resistance in HNC, such as hyperbaric oxygen treatment, accelerated radiotherapy with carbogen and nicotinamide, hypoxic cell radiosensitizers: nitroimi- dazoles, erythropoietin manipulation, and hypoxic cell cytotoxin. More recently, Micro-Environment-Vascular Normalization, HIF-1 Targeting and 18F-FMISO positron emission tomography-based intensity-modulated radiother- apy are promising methods.
Keywords Hypoxia • Radiotherapy • Head and neck cancer
• HIF-1
Tumor hypoxia, or the condition of low oxygen, is a key factor for tumor progression and treatment resistance. Hypoxia develops in solid tumors due to aberrant blood vessel forma- tion, fluctuation in blood flow, and increasing oxygen
demands for tumor growth. Because hypoxic tumor cells are more resistant to ionizing radiation, tumor hypoxia has been recognized as a potential cause of failure when treating human solid tumors with ionizing radiation, both in experi- mental models and in patients with several type of cancer including head and neck cancers (HNC). The importance of hypoxia as a potential mechanism limiting the probability of cure rate in patients with HNC treated with radiation has been recognized [1].